1.) To study the role of B-lymphoid progenitors in the development of systemic lupus using a combination of in vitro and in vivo approaches; 2.) To study the possible role of abnormal programmed cell death and altered growth regulation of B-progenitors in initiation of these events. Systemic lupus results from abnormal B-cell activation. A primary defect(s) present in bone marrow progenitor cells of lupus prone animals is essential in the initiation of this abnormal B-cell activation. Expression of the defect may be limited to B- and/or T-progenitors or, alternatively, affect multiple lineages. A candidate gene for this defect may affect apoptosis, the process of programmed cell death. For example, overexpression of Bcl-2, a proto-oncogene inhibiting apoptosis, results in systemic lupus erythematosus (SLE)-like disease and is one genetic model of systemic autoimmunity. We will investigate the role of abnormal apoptosis both as model for the development of systemic autoimmunity and as one possible genetic abnormality in SLE.